Exploring the influencing factors of scrub typhus in Gannan region, China, based on spatial regression modelling and geographical detector.

Scrub typhus is a significant public health issue with a wide distribution and is influenced by various determinants. However, in order to effectively eradicate scrub typhus, it is crucial to identify the specific factors that contribute to its incidence at a detailed level. Therefore, the objective of our study is to identify these influencing factors, examine the spatial variations in incidence, and analyze the interplay of two factors on scrub typhus incidence, so as to provide valuable experience for the prevention and treatment of scrub typhus in Gannan and to alleviate the economic burden of the local population.This study employed spatial autocorrelation analyses to examine the dependent variable and ordinary least squares model residuals. Additionally, spatial regression modelling and geographical detector were used to analyze the factors influencing the annual mean 14-year incidence of scrub typhus in the streets/townships of Gannan region from 2008 to 2021. The results of spatial1 autocorrelation analyses indicated the presence of spatial correlation. Among the global spatial regression models, the spatial lag model was found to be the best fitting model (log likelihood ratio = -319.3029, AIC = 666.6059). The results from the SLM analysis indicated that DEM, mean temperature, and mean wind speed were the primary factors influencing the occurrence of scrub typhus. For the local spatial regression models, the multiscale geographically weighted regression was determined to be the best fitting model (adjusted R2 = 0.443, AICc = 726.489). Further analysis using the MGWR model revealed that DEM had a greater impact in Xinfeng and Longnan, while the southern region was found to be more susceptible to scrub typhus due to mean wind speed. The geographical detector results revealed that the incidence of scrub typhus was primarily influenced by annual average normalized difference vegetation index. Additionally, the interaction between GDP and the percentage of grassland area had a significant impact on the incidence of scrub typhus (q = 0.357). This study illustrated the individual and interactive effects of natural environmental factors and socio-economic factors on the incidence of scrub typhus; and elucidated the specific factors affecting the incidence of scrub typhus in various streets/townships. The findings of this study can be used to develop effective interventions for the prevention and control of scrub typhus.

Scrub typhus meningoencephalitis in children: an experience from Eastern India.

Scrub typhus meningoencephalitis (STME) is an uncommon but fatal complication of scrub typhus that requires extra diligence in early identification and treatment. The goal of this study was to look at the clinical characteristics, laboratory results, and outcome of STME in children. A retrospective study was conducted in the paediatric intensive care unit of a tertiary care hospital in Eastern India between April 2021 and September 2022. It was carried out in children aged 1 month-12 years. Sixteen children were diagnosed with STME out of 75 acute encephalitis syndrome (AES) cases. The male-to-female ratio was 3:1, with a mean age of 4.28 ± 3.36 years. All the children hailed from rural areas. Fever (100%), convulsions (87.5), altered sensorium (93.75%), nuchal stiffness (25%), vomiting (75%), pallor (75%), and hepatomegaly (50%) were the most prevalent clinical manifestations. The average duration of fever upon presentation was 8.25 ± 2.11 days and the average length of hospital stay was 9.00 ± 4.59 days. The complications encountered were shock (3), interstitial pneumonia (1), myocarditis (1), raised intracranial pressure (1), and right-sided hemiplegia (1). Fifteen children recovered completely, whereas one child suffered from residual right-sided neurodeficit. A high index of suspicion needs to be maintained for STME as a possible AES entity, as anti-scrub measures administered promptly can go a long way in mitigating the related morbidity and mortality especially in resource-constrained settings.

Predicting Secondary Hemophagocytic Lymphohistiocytosis in Adult Patients with Scrub Typhus and Its Prognostic Significance.

Objective: Secondary hemophagocytic lymphohistiocytosis (sHLH) is an increasingly recognized complication in patients with scrub typhus, potentially contributing to substantial mortality despite appropriate antibiotic treatment. This study aims to determine the prevalence and prognosis of sHLH and identify diagnostic factors in adult patients with scrub typhus in North India. Methods: This prospective cohort study was conducted at PGIMER, Chandigarh, from August 2021 to November 2023. sHLH was defined as an HScore of 200 or above. The diagnostic performance of biomarkers such as ferritin, fibrinogen, triglycerides, and C-reactive protein was assessed through receiver operating characteristic curve analysis, evaluating area under the curve (AUC), sensitivity, and specificity. Results: Out of 150 patients (mean age 39 years, 54% female), 28 (18.7%) were diagnosed with sHLH. Those presenting with high-grade fever, seizures, high pulse rate, hepatomegaly, splenomegaly, cytopenia, and significant hepatic dysfunction were more likely to have sHLH. Ferritin demonstrated the highest diagnostic utility (AUC 0.83), compared to fibrinogen (AUC 0.72), triglyceride (AUC 0.67), and C-reactive protein (AUC 0.69). The optimal cutoff for ferritin was 2000 ng/mL, with a sensitivity of 90% and a specificity of 66%. Higher ferritin thresholds (6000 ng/mL and 10000 ng/mL) increased specificity to 88% and 95%, respectively. Patients with sHLH often presented with multi-organ failure, necessitating mechanical ventilation and vasopressor support. In-hospital mortality was significantly higher in sHLH patients than in those without (21.4% vs 6.6%, p = 0.025). Conclusion: Early detection of sHLH using the HScore and ferritin significantly influences the management of scrub typhus, underscoring the necessity for tailored therapeutic strategies to improve patient outcomes. How to cite this article: Selvam S, Tuli A, Yuvasai KP, Saini S, Erla SR, Kaur J, et al. Predicting Secondary Hemophagocytic Lymphohistiocytosis in Adult Patients with Scrub Typhus and Its Prognostic Significance. Indian J Crit Care Med 2024;28(9):823-831.

The HScore to Diagnose HLH in Scrub Typhus: Overdiagnosis or under Diagnosis and Does It Really Matter?

How to cite this article: Hegde A. The HScore to Diagnose HLH in Scrub Typhus: Overdiagnosis or under Diagnosis and Does It Really Matter? Indian J Crit Care Med 2024;28(9):811-812.

Estimation of scrub typhus incidence and spatiotemporal multicomponent characteristics from 2016 to 2023 in Zhejiang Province, China.

Background: China is one of the main epidemic areas of scrub typhus, and Zhejiang Province, which is located in the coastal area of southeastern China, is considered a key region of scrub typhus. However, there may be significant bias in the number of reported cases of scrub typhus, to the extent that its epidemiological patterns are not clearly understood. The purpose of this study was to estimate the possible incidence of scrub typhus and to identify the main driving components affecting the occurrence of scrub typhus at the county level. Methods: Data on patients with scrub typhus diagnosed at medical institutions between January 2016 and December 2023 were collected from the China Disease Control and Prevention Information System (CDCPIS). The kriging interpolation method was used to estimate the possible incidence of scrub typhus. Additionally, a multivariate time series model was applied to identify the main driving components affecting the occurrence of scrub typhus in different regions. Results: From January 2016 to September 2023, 2,678 cases of scrub typhus were reported in Zhejiang Province, including 1 case of reported death, with an overall case fatality rate of 0.04%. The seasonal characteristics of scrub typhus in Zhejiang Province followed an annual single peak model, and the months of peak onset in different cities were different. The estimated area with case occurrence was relatively wider. There were 41 counties in Zhejiang Province with an annual reported case count of less than 1, while from the estimated annual incidence, the number of counties with less than 1 case decreased to 21. The average annual number of cases in most regions fluctuated between 0 and 15. The numbers of cases in the central urban area of Hangzhou city, Jiaxin city and Huzhou city did not exceed 5. The estimated random effect variance parameters σ λ 2 , σ ϕ 2 , and σ ν 2 were 0.48, 1.03 and 3.48, respectively. The endemic component values of the top 10 counties were Shuichang, Cangnan, Chun'an, Xinchang, Pingyang, Xianju, Longquan, Dongyang, Yueqing and Qingyuan. The spatiotemporal component values of the top 10 counties were Pujiang, Anji, Pan'an, Dongyang, Jinyun, Ninghai, Yongjia, Xiaoshan, Yinwu and Shengzhou. The autoregressive component values of the top 10 counties were Lin'an, Cangnan, Chun'an, Yiwu, Pujiang, Longquan, Xinchang, Luqiao, Sanmen and Fuyang. Conclusion: The estimated incidence was higher than the current reported number of cases, and the possible impact area of the epidemic was also wider than the areas with reported cases. The main driving factors of the scrub typhus epidemic in Zhejiang included endemic components such as natural factors, but there was significant heterogeneity in the composition of driving factors in different regions. Some regions were driven by spatiotemporal spread across regions, and the time autoregressive effect in individual regions could not be ignored. These results that monitoring of cases, vectors, and pathogens of scrub typhus should be strengthened. Furthermore, each region should take targeted prevention and control measures based on the main driving factors of the local epidemic to improve the accuracy of prevention and control.

Unveiling the burden of scrub typhus in acute febrile illness cases across India: A systematic review & meta-analysis.

Background & objectives Scrub typhus is an emerging mite-borne zoonotic infection that has been overlooked, despite being one of the most widespread severe vector-borne diseases. With an estimated one billion people at risk worldwide and one million annual cases, it poses a significant public health concern. While various studies have investigated the prevalence of scrub typhus in different regions of India, a comprehensive regional systematic review and meta-analysis on the seropositivity of scrub typhus among acute febrile cases has been lacking. To address this gap, we conducted a systematic review and meta-analysis to compile information on the current seroprevalence of scrub typhus in acute febrile illness cases in India. Methods A literature search of multiple databases on prevalence of scrub typhus in acute febrile illness in India, 60 eligible studies out of 573 studies. The prevalence of individual studies was double arcsine transformed, and the pooled prevalence was calculated using inverse variance method. Results In total, these studies encompassed 34,492 febrile cases. The overall seroprevalence of scrub typhus among acute febrile illness cases in India was found to be 26.41 per cent [95% confidence interval (CI): 22.03-31.03]. Additionally, the pooled case fatality rate (based on data from six studies) among scrub typhus-positive cases yielded a case fatality rate of 7.69 per cent (95% CI: 4.37-11.72). Interpretation & conclusions This meta-analysis shows that scrub typhus is a significant health threat in India. Preventive measures to control scrub typhus need to be given priority.

A systematic review of environmental covariates and methods for spatial or temporal scrub typhus distribution prediction.

BACKGROUND: Scrub typhus is underdiagnosed and underreported but emerging as a global public health problem. To inform future burden and prediction studies we examined through a systematic review the potential effect of environmental covariates on scrub typhus occurrence and the methods which have been used for its prediction. METHODS: In this systematic review, we searched PubMed, Scopus, Web of Science, China National Knowledge Infrastructure and other databases, with no language and publication time restrictions, for studies that investigated environmental covariates or utilized methods to predict the spatial or temporal human. Data were manually extracted following a set of queries and systematic analysis was conducted. RESULTS: We included 68 articles published in 1978-2024 with relevant data from 7 countries/regions. Significant environmental risk factors for scrub typhus include temperature (showing positive or inverted-U relationships), precipitation (with positive or inverted-U patterns), humidity (exhibiting complex positive, inverted-U, or W-shaped associations), sunshine duration (with positive, inverted-U associations), elevation, the normalized difference vegetation index (NDVI), and the proportion of cropland. Socioeconomic and biological factors were rarely explored. Autoregressive Integrated Moving Average (ARIMA) (n = 8) and ecological niche modelling (ENM) approach (n = 11) were the most popular methods for predicting temporal trends and spatial distribution of scrub typhus, respectively. CONCLUSIONS: Our findings summarized the evidence on environmental covariates affecting scrub typhus occurrence and the methodologies used for predictive modelling. We review the existing knowledge gaps and outline recommendations for future studies modelling disease prediction and burden. TRIAL REGISTRATION: PROSPERO CRD42022315209.

Changes in seasonality and sex ratio of scrub typhus: a case study of South Korea from 2003 to 2019 based on wavelet transform analysis.

BACKGROUND: Scrub typhus (ST, also known as tsutsugamushi disease) is a common febrile vector-borne disease in South Korea and commonly known as autumn- and female-dominant disease. Although understanding changes in seasonality and sex differences in ST is essential for preparing health interventions, previous studies have not dealt with variations in periodicity and demographic characteristics in detail. Therefore, we aimed to quantify the temporal dynamics of seasonal patterns and sex differences in the incidence of ST in South Korea. METHODS: We extracted epidemiological week (epi-week)-based ST cases from 2003 to 2019 Korean National Health Insurance Service data (ICD-10-CM code: A75.3). To determine changes in seasonality and sex differences, year-, sex-, and age-group-stratified male-to-female ratios and wavelet transform analyses were conducted. RESULTS: Between 2003 and 2019, 213,976 ST cases were identified. The incidence per 100,000 population increased by 408.8% from 9.1 in 2003 to 37.2 in 2012, and subsequently decreased by 59.7% from 2012 to 15.0 in 2019. According to the continuous wavelet transform results, ST exhibited a dual seasonal pattern with dominant seasonality in autumn and smaller seasonality in spring from 2005 to 2019. Overall, the periodicity of seasonality decreased, whereas its strength decreased in autumn and increased in spring. With an overall male-to-female ratio being 0.68:1, the ratio has increased from 0.67:1 in 2003 to 0.78:1 in 2019 (Kendall's τ = 0.706, p < 0.001). However, interestingly, the ratio varied significantly across different age groups. CONCLUSIONS: Our findings quantitatively demonstrated changes in seasonality with dual seasonal pattern and shortened overall periodicity and a decrease in sex differences of ST in South Korea. Our study suggests the need for continuous surveillance on populations of vector and host to address ST dynamics to preemptively prepare against global warming.

Estimating the Seroprevalence of Scrub Typhus in Nepal.

Prior to the devastating earthquake in Nepal in 2015, scrub typhus was not recognized as a highly endemic disease in the country. This contrasted with neighboring India, where scrub typhus is endemic and there have been sporadic outbreaks of severe forms. This discrepancy underscores the limitations in our comprehensive understanding of the scrub typhus epidemiological patterns in Nepal, especially before 2015. To better understand the dynamic and current status of scrub typhus, this study investigated its prevalence among patients with acute febrile illness in two hospitals located in Pokhara city, Kaski district and Bharatpur city, Chitwan district during 2009-2010. Our findings revealed that 31.5% (239 of 759 patients) of the cases were positives for scrub typhus based on serological and pathogen detection assays. These results provide crucial insights into the pre-earthquake endemicity of scrub typhus in Nepal, implying its long-standing presence in the region prior to the significant environmental transformations caused by the 2015 earthquake. This study also emphasizes the need for heightened awareness and improved diagnostic capabilities to effectively manage and control scrub typhus, which remains a significant public health concern in Nepal.

Cerebral Venous Sinus Thrombosis Following Scrub Typhus Meningoencephalitis in a Pregnant Woman.

Background: Scrub typhus, a mite-borne zoonosis caused by Orientia tsutsugamushi, is prevalent in the Asia Pacific region and presents with various neurological manifestations, including meningoencephalitis, polyneuropathy, and, rarely, cerebral venous sinus thrombosis (CVST). Case Report: We report a unique case of CVST following scrub typhus meningoencephalitis in an 18-year-old pregnant woman from West Bengal, India. Her condition was complicated by fever, headache, neck stiffness, and altered sensorium. Laboratory tests revealed leukopenia and thrombocytopenia, while serologies for other infectious diseases were negative. Cerebrospinal fluid analysis was significant for lymphocytic pleocytosis and elevated protein, with a positive O tsutsugamushi-IgM assay. Treatment with azithromycin resulted in initial improvement; however, persistent headaches led to the discovery of CVST. The patient responded well to anticoagulation therapy with low molecular weight heparin and was discharged asymptomatic, with subsequent uneventful pregnancy and delivery. Discussion: Cerebral venous sinus thrombosis should be ruled out in pregnant women with refractory scrub typhus meningoencephalitis despite antibiotic therapy. Because scrub typhus is treatable with intravenous doxycycline and azithromycin, it should be considered in the workup of febrile patients with acute onset neurological disorders in the tropics or subtropics or travelers coming back from endemic areas, despite the absence of eschar and unremarkable neuroimaging findings.

Frequency and distribution of eschar in patients with scrub typhus in India: systematic review of literature and meta-analysis.

Introduction: Scrub typhus is a mite-borne tropical febrile illness with high mortality if untreated. The presence of eschar is pathognomonic, but a wide range of frequencies of eschar positivity has been reported in Indian patients. Therefore, this systematic review and meta-analysis aimed to ascertain the frequency (overall and geographic region-wise) and anatomical distribution of eschar in scrub typhus in India. Methodology: We searched articles in two databases using: [(scrub OR typhus OR Orientia) AND (eschar) AND (India)]. The articles were independently screened and critically appraised by two authors. The frequency and distribution of eschar in patients with scrub typhus were pooled using a random-effect model. Results: After the title-abstract and full-text screening, 107 articles (34002 cases of scrub typhus) were finally included. The overall pooled proportion of eschar positivity was 28.5% (95% CI: 24.1 to 32.9%). The pooled eschar positivity varied from ≤12% in Haryana, Rajasthan, Madhya Pradesh, Punjab, and Meghalaya to ≥46% in Tamil Nadu and Tripura. The pooled proportion of eschar positivity in the 'trunk' (39.3%), 'groin' (23.8%), and 'axilla' (16.5%) was higher than in the 'limbs' (9.9%) and 'head' (11.3%). Conclusion: Eschar is reported in less than a third of the patients with scrub typhus in India. Most eschars were in the groin, axilla, and the trunk. There is a need to create awareness amongst physicians of the need for thorough physical examination.

Peripartum Infections: A Position Statement of the Indian Society of Critical Care Medicine.

This position statement reviews the evidence and rationale for the management of severe peripartum infections with a special focus on tropical infections and is tailored for resource-limited settings. How to cite this article: Samavedam S, Sodhi K, Anand P, Bajwa SJS, Karnad DR, Karanth S, et al. Peripartum Infections: A Position Statement of the Indian Society of Critical Care Medicine. Indian J Crit Care Med 2024;28(S2):S92-S103.

Foetal outcome of Leptospira and Rickettsial infections during pregnancy: a systematic review.

BACKGROUND: Leptospirosis and rickettsial infections are bacterial zoonoses prevalent in different geographical locations and presents with overlapping symptoms. OBJECTIVE: To identify foetal outcomes in pregnant women diagnosed with rickettsial infections, including scrub typhus and leptospirosis, along with their associated factors. METHODS: A comprehensive search was conducted in MEDLINE/PubMed, Scopus, CENTRAL (Cochrane), Web of Science, PsycINFO, Academic Search Premier, CINAHL, and Embase using defined search terms. Studies involving pregnant women with diagnosed leptospirosis and rickettsial infections, including scrub typhus, were selected. Two independent reviewers screened titles and abstracts using the Rayyan Web interface. Data extraction was performed in Microsoft Excel, with Zotero for reference management. Study quality was assessed using Joanna Briggs Institute Critical Appraisal tools. Data synthesis included narrative analysis. RESULTS: Fifty-four studies were included: 22 on scrub typhus, 14 on rickettsial infection, 16 on leptospirosis, and 2 on all three infections. Of 176 scrub typhus cases, 53 resulted in foetal loss and 3 in neonatal death. Among 38 rickettsial infection cases, 4 had foetal loss. Out of 63 leptospirosis cases, 13 experienced foetal loss. Six maternal deaths occurred due to scrub typhus and one due to Rocky Mountain spotted fever. CONCLUSION: Leptospirosis and rickettsial infections, including scrub typhus, are important causes of pregnancy loss. Further research is needed to better understand and mitigate these risks in pregnant women.

Prevalence, Clinico-Laboratory Features and Outcomes of Paediatric Scrub Typhus Cases in a Tertiary Care Centre in Eastern India: A prospective observational study.

Objectives: Scrub typhus is the most common rickettsial disease in India, caused by Orientia tsutsugamushi and transmitted by chigger mites. Previously prevalent in South India, a resurgence of scrub typhus cases has recently affected Eastern India. This study aimed to estimate the prevalence and describe the clinico-laboratory profile of scrub typhus in paediatric patients (1-12 years old) living in Eastern India. Methods: This prospective observational study was conducted from January to December 2019 at the Dr B C Roy Post Graduate Institute of Paediatric Sciences, Kolkata, India. All acute undifferentiated cases of febrile illness, in patients aged between 1-12 years, were tested using scrub typhus serology by ELISA. Demographic details, clinical features, laboratory findings, complications and treatment outcomes of these scrub typhus patients were extracted and analysed. Results: Out of 1,473 patients with acute febrile illness, 67 (4.5%) children were diagnosed with scrub typhus. The mean age of the selected patients was 5.22 ± 3.05 years, and the majority (64.2%) had been running a fever since the preceding 7-14 days. Gastrointestinal symptoms such as vomiting (43.3%) and abdominal pain (32.8%) were most frequently observed. Major clinical signs of scrub typhus were hepatomegaly (41.8%) and splenomegaly (31.3%). Complications were observed in 74.6% of patients, with thrombocytopenia (40.3%) and meningoencephalitis (29.9%) occurring more frequently. The case fatality rate of the study sample was 1.5%. Conclusion: Classical eschar was absent in three-fourth of the studied patients. Hence, this study advocates laboratory scrub typhus tests for all suspected cases in the endemic region (Eastern India). Prompt treatment with doxycycline and/or azithromycin could prevent complications such as thrombocytopenia/meningoencephalitis and reduce mortality.

Predictors of mortality in scrub typhus: A hospital-based study.

Purpose: Scrub typhus is a potentially life-threatening febrile illness associated with serious complications viz. pneumonia, acute respiratory distress syndrome, hepatic failure, acute kidney injury, encephalitis, and shock often culminating in mortality. We aimed to identify the predictors of mortality in scrub typhus. Methods: This prospective observational study was conducted in a tertiary referral hospital of the north Indian state of Uttarakhand on in-patients of scrub typhus hospitalized over 1 year. Results: Of the 109 cases studied (54.1% males), 44% were aged <40 years. Fever (95.4%), loss of appetite (55.9%), myalgia (47.7%), pallor (40.3%), hepatomegaly (27.5%), eschar (17.4%), and splenomegaly (13.7%) were the main clinical features. Hepatic transaminitis (69.7%), renal insufficiency (44.0%), respiratory failure (37.6%), shock (33.9%), central nervous system (CNS) involvement (21.1%), and severe anemia (7.3%) were the major complications at presentations. Intensive care and mechanical ventilation were utilized in 33.9% and 15.5% of cases, respectively. Multivariate logistic regression suggested renal insufficiency, CNS involvement, shock, severe anemia, and mechanical ventilation independently associated with death. Conclusion: Respiratory failure, renal insufficiency and neurological involvement, mechanical ventilation, shock, and severe anemia at presentation predict mortality in scrub typhus.

Omadacycline in the treatment of scrub typhus: Three case reports.

BACKGROUND: Scrub typhus is a naturally occurring acute infectious disease that is primarily transmitted through the bites of chiggers or larval mites infected by Orientia tsutsugamushi (O. tsutsugamushi). Omadacycline, a novel tetracycline, exhibits potent antibacterial efficacy against both typical bacteria and atypical pathogens. However, omadacycline application in the treatment of scrub typhus remains limited. CASE SUMMARY: In the present work, we report several cases of scrub typhus, with the main clinical symptoms being fever, the formation of eschars or ulcers, local or systemic lymphadenopathy, headache, myalgia and rash. Blood samples were collected before omadacycline was administered, and O. tsutsugamushi infection was confirmed through targeted next-generation sequencing (tNGS). After two days of treatment, the patients' symptoms, including fever, were alleviated, with no adverse drug reactions. CONCLUSION: tNGS is an effective method for diagnosing scrub typhus. Omadacycline can be considered an alternative option for antiinfective therapy in patients with O. tsutsugamushi infections.

Utility of next-generation sequencing for the etiological diagnosis of Orientia tsutsugamushi infection.

Background: Scrub typhus, an acute febrile disease caused by Orientia tsutsugamushi, is transmitted to humans through infected chigger mites. We present a case of scrub typhus in a previously healthy man from Shandong Province diagnosed using next-generation sequencing (NGS) and PCR and review recent literature on NGS for scrub typhus diagnosis. Methods: NGS was utilized for testing whole blood collected on admission. Confirmatory testing was done by detecting IgM and IgG antibodies to Orientia in acute and convalescent sera by ELISA. Orientia 47-kDa protein gene TaqMan and standard PCR of the 56-kDa protein gene and Sanger sequencing were performed on eschar scab DNA. Results: The NGS diagnosis was confirmed by 47-kDa protein gene TaqMan and sequencing of a fragment of the O. tsutsugamushi 56-kDa protein gene from the eschar scab. Analysis of this sequence and the NGS data indicated O. tsutsugamushi strain Cheeloo2020 is a novel genotype. Mapping of the NGS data against the O. tsutsugamushi Gilliam strain genome sequence identified 304 reads with high similarity. Conclusions: NGS is not only useful for multiplex diagnosis of scrub typhus, but also provides insight into the genetic diversity of O. tsutsugamushi. The common failure to submit sequences to databases makes it difficult to determine the minimal quantity and quality of NGS data being used for the positive identification of Orientia DNA in clinical specimens.

Orientia tsutsugamushi infection reduces host gluconeogenic but not glycolytic substrates.

Orientia tsutsugamushi a causal agent of scrub typhus, is an obligate intracellular bacterium that, akin to other rickettsiae, is dependent on host cell-derived nutrients for survival and thus pathogenesis. Based on limited experimental evidence and genome-based in silico predictions, O. tsutsugamushi is hypothesized to parasitize host central carbon metabolism (CCM). Here, we (re-)evaluated O. tsutsugamushi dependency on host cell CCM as initiated by glucose and glutamine. Orientia infection had no effect on host glucose and glutamine consumption or lactate accumulation, indicating no change in overall flux through CCM. However, host cell mitochondrial activity and ATP levels were reduced during infection and correspond with lower intracellular glutamine and glutamate pools. To further probe the essentiality of host CCM in O. tsutsugamushi proliferation, we developed a minimal medium for host cell cultivation and paired it with chemical inhibitors to restrict the intermediates and processes related to glucose and glutamine metabolism. These conditions failed to negatively impact O. tsutsugamushi intracellular growth, suggesting the bacterium is adept at scavenging from host CCM. Accordingly, untargeted metabolomics was utilized to evaluate minor changes in host CCM metabolic intermediates across O. tsutsugamushi infection and revealed that pathogen proliferation corresponds with reductions in critical CCM building blocks, including amino acids and TCA cycle intermediates, as well as increases in lipid catabolism. This study directly correlates O. tsutsugamushi proliferation to alterations in host CCM and identifies metabolic intermediates that are likely critical for pathogen fitness.IMPORTANCEObligate intracellular bacterial pathogens have evolved strategies to reside and proliferate within the eukaryotic intracellular environment. At the crux of this parasitism is the balance between host and pathogen metabolic requirements. The physiological basis driving O. tsutsugamushi dependency on its mammalian host remains undefined. By evaluating alterations in host metabolism during O. tsutsugamushi proliferation, we discovered that bacterial growth is independent of the host's nutritional environment but appears dependent on host gluconeogenic substrates, including amino acids. Given that O. tsutsugamushi replication is essential for its virulence, this study provides experimental evidence for the first time in the post-genomic era of metabolic intermediates potentially parasitized by a scrub typhus agent.

C-C Motif Ligand 7 (CCL7) and C-C Motif Chemokine Receptor 3 (CCR3) dysregulation in patients with scrub typhus and association with mortality.

BACKGROUND: Scrub typhus, caused by Orientia tsutsugamushi involves infiltration of a mixture of perivascular lymphocytes and macrophages into affected organs. We investigated if this is characterized by chemokine dysregulation. METHODS: mRNA expression of chemokines and receptors were screened in whole blood by cDNA microarray in a subgroup of patients and controls. Regulated transcripts were analyzed in plasma by enzyme immunoassays (chemokines) and in whole blood by qPCR (receptors) from scrub typhus patients (n=129), patients with similar febrile illness without Orentia tsutsugamushi infection (n=31) and healthy controls (n=31). RESULTS: (i) cDNA microarray identified dysregulation of the chemokines CCL18 and CCL23 and CCR3 receptor, in severe scrub typhus. (ii) Plasma CCL7, a ligand for CCR3, CCL18 and CCL23 were higher in scrub typhus patients, with a decline during follow-up. (iii) Conversely, mRNA levels of CCR3 and CCR8, the receptor for CCL18, were decreased in whole blood at hospital admission followed by an increase during follow-up. (iv) CCL7 was independently associated with disease severity. (v) Admission CCL7 levels were associated with short-time mortality. CONCLUSION: Our findings suggest CCL7 could represent a hitherto unknown pathogenic mediator in Orentia tsutsugamushi infection contributing to local and systemic inflammation.

Various Presentations of Scrub Typhus: A Case Series.

Scrub typhus is caused by Orientia tsutsugamushi, a Gram-negative coccobacillus. It comprises three strains: Karp, Gilliam, and Kato. Cases of scrub typhus are usually found in the Asia-Pacific region, and their presentation may range from minimal symptoms to multi-organ involvement, with or without the presence of an eschar mark. Varying manifestations of scrub typhus, such as gangrene, meningoencephalitis, anemia with jaundice, and hematuria, have been observed. In the Kumaun region of northern India, there has been a surge in the number of scrub typhus cases. Typically, this disease is accompanied by an eschar mark, but occasionally it can manifest without one. We report a series of four cases presenting with various unusual symptoms such as gangrene of the limbs, meningoencephalitis, jaundice, and hematuria. Serology for scrub typhus should be considered in all patients with acute febrile illness not responding to treatment, especially in mountainous regions, to prevent the associated mortality.